This invention pertains to a method of identifying patients with brain tumors and to determine the response of patients to treatment. The method of the invention can distinguish patients with malignant primary and metastatic brain tumors by measuring the increase of lipid associated sialoprotein (LSP) in the cerebrospinal fluid (CSF). The invention also can determine the response to treatment and therefore it can be used to monitor radiation and chemotherapy.
There exist other methods and procedures for distinguishing patients with malignant brain tumors from benign tumors. However, these methods typically require tumor tissue which is not practical on a routine basis or sophisticated equipment such as MRI spectroscopy which is expensive and not widely available. On the other hand, CSF is easily and safely accessible in nearly all patients and can be examined at reasonably frequent intervals without comprising a patient's safety. Moreover, MRI scanning is frequently unrevealing or equivocal with respect to early indications of central nervous system attack by systemic tumor metastasis.
The method of the invention whereby LSP is measured in the CSF has been shown to provide an early indicator of central nervous system involvement. Prior to the method of the invention there has been no specific tumor marker for brain cancer. Moreover, the method of the invention is extremely cost effective, particularly when compared with the significant cost associated with an MRI examination.
More than one hundred thousand new cases of brain tumors were diagnosed in 1998. By the time the symptoms appear most tumors have infiltrated widely and surgery, cranial irradiations and chemotherapy can provide only questionable benefit. Diagnosis of brain tumors generally occur after the onset of neurologic manifestations. By that time the tumor is well established and for the vast majority of patients this is fatal. Modern neuroimaging techniques such as magnetic resonance imaging (MRI), spectroscopy, and position emission tomography have facilitated early diagnosis. However, these studies are expensive and cumbersome and are limited by false negative and false positive findings in a number of common situations including radiation necrosis, central nervous system infections, or vascular malformations. A convenient, reliable and efficient screening test which can detect brain metastases at an early stage to initiate treatment in patients at high risk has not been currently available. Also lacking is a reliable method to detect tumor reoccurrence, predict response to therapy, and distinguish between persistent or recurrent tumor and treatment related changes in patients with primary brain tumors.
A number of antigens have been suggested as tumor serologic markers. For example, there are squamous cell carcinoma antigen, prostate specific antigen, carcinoma embryonic antigen, and antigens labeled CA 125 for ovarian cancer, CA 153 for breast cancer and CA 19-9 for pancreatic cancer. These markers are serologic markers identified in the blood for systemic tumors but no such markers have been found in the blood of patients with primary brain tumors. Most brain tumor markers reflect chromosomal abnormalities such as gene mutations, translocations, and fibroblasts growth factor expression. However, these markers are determined only when biopsy specimens are obtained and the tumors themselves are analyzed. They are not useful as diagnostic aids or to assess a response to ongoing therapy.
The method of the invention makes use of cerebro spinal fluid (CSF) as a source of biological indicators that can provide information regarding the presence of a tumor in the CSF and its status. The method of the invention shows that CSF contains specific markers which provide a basis for evaluating the presence of a tumor in the CSF or its activity.
It has long been known that tumor cells have caused changes in the metabolism of sialic acid. These changes result in larger amounts of sialic acid being present on the surface of malignant tumor cells compared to benign tumor cells.
It was suggested that Sialic Acid (S.A.) might be a useful tumor marker 25 years ago when a new protein lipid complex was identified in rats with Walker adenocarcinoma. In 1977 Kloppel and his collaborators for the first time used serum S.A. as a marker for cancer. The most commonly used method is one developed by Katopodis e. al. LSA has been found to be more reliable than other markers in identifying patients with head and neck cancer, localized and metastatic prostate cancer, lung cancer, leukemia, lymphoma, Hodgkins' lymphoma, melanoma and others.
These serologic markers of the prior art are principally identified in the blood for systemic tumors. The method of the invention makes use of the CSF and has determined that material produced by the tumor or the surrounding cells in response to the tumor are diffused into the CSF.